Coronary Heart Disease Risk Factors (CHDRFs) are major causes of death in the industrialized world. CHD risk factors include Type 2 Diabetes (and its precursor, Impaired Glucose Tolerance (IGT)), hyperlipidemia or dyslipidemia, overweight, obesity and essential hypertension, i.e., a form of hypertension that occurs without a discoverable organic cause. The CHDRF syndrome may, therefore, be defined as a group of interrelated disorders: Type 2 Diabetes, IGT, Dyslipidemia, Overweight, Obesity and essential hypertension. It has also become apparent that Type 2 Diabetes, by itself, represents a syndrome of various, in part sequential, disease states which interact with other components of the CHDRF syndrome. However, the exact interrelationships between the disease states that make up these syndromes are not fully understood. A wide variety of chemical and physical abnormalities associated with these syndromes exist. They include elevations in fasting blood glucose and gluconeogenesis in spite of significant increases in fasting insulin and C-peptide concentrations and increases in lipogenesis. Typically associated with lipogenesis are increases in levels of fasting Free Fatty Acid (FFA), fasting triglycerides (TG) and total cholesterol concentrations, increases in levels of fasting Low Density Lipoprotein (LDL)-cholesterol, decreases in levels of fasting High Density Lipoprotein (HDL)-cholesterol, an increased LDL/HDL ratio, increases in body weight and increases in systolic and diastolic blood pressure.
Although these syndromes are interrelated and typically result from derangements in nutrient metabolism, all the associated symptoms may not be present in individual patients. Accordingly, in some patients lipid metabolism problems may predominate, while in others, carbohydrate metabolism problems may be predominant. While these factors, which lend one aspect of the syndrome to dominate over another, are not well understood, it is clear that each portion of the syndrome, or combinations of portions of the syndrome, represents risk factors in coronary heart disease.
Insulin Resistance/Beta-Cell Dysfunction/Type 2 Diabetes/CHDRF Syndrome
Common denominators in the etiology of the syndromes of Type 2 Diabetes and the CHDRFs appear to be Insulin Resistance (IR) and Beta-Cell Dysfunction. IR is characterized as a state in which a normal amount of insulin produces a subnormal biological response in carbohydrate metabolism. This may be the case for subjects afflicted with the non-insulin-dependent diabetes form of Type 2 Diabetes, in pre-diabetic subjects affected by Impaired Fasting Glucose (IFG) or Impaired Glucose Tolerance (IGT), and in overweight and obese subjects. These subjects require (and endogenously produce) higher than normal levels of insulin to compensate for their insulin resistance and Beta-Cell Dysfunction to normalize their blood glucose levels. Traditionally, IR has been expressed as the insulin/glucose ratio (I/G). More recently, several more complex models have been proposed to define Insulin Resistance or the Insulin Sensitivity Index. Only recently have other biological functions of insulin become the focus of more intense scientific interest, e.g. the role of insulin in endogenous lipogenesis. Although an interaction between insulin resistance and the CHDRF components has been established, the cause and effect relationship between insulin resistance, obesity, dyslipidemia and IGT/Type 2 Diabetes is still subject to debate. IR increases FFA and Triglyceride (TG) levels, which further contribute to IR, thereby creating a vicious circle. Therapeutic modalities for lowering any one of the lipid fractions in dyslipidemia have not proven capable of correcting the entire hyperlipidemic complex with a single therapeutic agent.
Compared to Type 1 juvenile) Diabetes, the Type 2 Diabetes syndrome, particularly its non-insulin-dependent mellitus (NIDDM) forms, is characterized by relatively inadequate endogenous insulin concentrations. However, insulin concentrations in Type 2 diabetics may, in fact, be higher than in the normal population. A possible explanation for this apparent discrepancy is that Type 2 diabetics, as well as subjects afflicted with IFG, IGT, Overweight or Obesity typically require more insulin to control their blood sugar levels. Temporary increases in certain diabetogenic mediators, such as glucagon, growth hormones and catecholamines may initially cause the requirement for more insulin. These mediators communicate their specific control functions as agonists to target tissue or cells through compatible cell bound receptors. Continued, long-term agonist load eventually leads to ‘down-regulation’ of such receptors, i.e. the receptor response and/or sensitivity are decreased. Depending on the agonist involved, this mechanism can lead to tolerance or addiction. As a result, increasing doses are required to achieve the same effect. Antagonists have equivalent receptor specificity as their agonist counterparts, but do not convey any agonist-type control message. In contrast to agonists, prolonged exposure of such receptors to their specific antagonists can restore receptor response or sensitivity, a process called receptor ‘up-regulation’.
As long as any agonists load by mediators, such as hormones, neuro-transmitters or neuro-modulators prevails for infrequent, short durations, the respective receptors for such mediators can ‘up-regulate’ between such temporary agonist loads. In other words, the receptors can resume their normal sensitivity between ‘receptor-ligand’ interactions. The early stage of IR may be characterized by temporary increases in diabetogenic mediators such as catecholamines, endogenous opiates, cortisol and/or glucagon.
Another early pathophysiologic indicator of the emergence of the CHDRF Syndrome is a condition called Beta-Cell Dysfunction. Non-diabetics experience a bi-phasic insulin response to an oral glucose challenge, i.e. an acute, first phase governed by a rise in blood glucose, and second, proportional phase characterized by a more sustained insulin release, following, in a quasi proportional manner, the post-prandial glucose excursion. Overweight and IGT subjects already have a significantly reduced first phase insulin release, which virtually disappears altogether once the subject becomes obese and or diabetic. This condition exaggerates the Insulin Resistance related hyperglycemia and hyperinsulinemia and accelerates the severity of the CHDRF Syndrome.
The impairment or loss of first phase insulin secretion is the primary defect in BetaCell Dysfunction
A pharmacologic restoration of the vitally important first phase insulin release has, to this date, been an elusive scientific undertaking.
Resistance to the action of insulin in the control of glucose may not carry over to the action of insulin on lipogenesis. Even though the individual is resistant to the action of insulin in controlling glucose, the response of lipid metabolism to insulin may remain at the normal level. As temporary agonist ‘loads’ become more frequent or sustained, the affected receptors will down-regulate. As a result, IR may become a permanent metabolic burden and, with additional diabetogenic factors, such as cortisol, may accelerate progressive increases in hepatic gluconeogenesis (GNG) and glucose production (GP). The IR dependent insulin excess in the face of hyper-gluconeogenesis caused hyperglycemia then becomes a blueprint for hyper- or dyslipidemia, overweight and obesity. Gradually, the β-cells' secretory capacity to produce and secrete insulin will diminish, resulting in a slow but steady rise in fasting glucose levels until, eventually, such secretory capacity will be exhausted, at which time the subject becomes ‘insulin dependent’, i.e. dependent on exogenous insulin injections.
Dyslipidemia
Dyslipidemia is characterized by any of the following, and combinations thereof: elevated levels of total and LDL-cholesterol, elevated levels of TG, a high LDL/HDL ratio and elevated levels of FFA and low levels of HDL-cholesterol. Lipid metabolism is rather complex. While it is clear that dyslipidemia is associated with the development of coronary heart disease, there is no clear understanding of the pathogenic causes and pathways leading up to the manifestation of the various lipid disorders. The relative roles of lipid ingestion versus endogenous lipogenesis in the etiology of lipid abnormalities have not been fully understood.
Overweight/Obesity
Obesity is a disease of major proportions and severe economic consequences. No longer is obesity considered merely a physical or cosmetic inconvenience. Obesity is second only to cigarette smoking as a preventable cause of premature death, and its complications add in excess of $100 billion to U.S. health care costs. Obesity can not be treated effectively by willpower alone, and currently available pharmaceutical drugs are only marginally effective. Moreover, several obesity drugs have recently been withdrawn from the market because of their risk of potentially fatal side-effects, e.g. pulmonary hypertension or heart defects in connection with dexfenfluramine, fenfluramine or phentermine.
Six out of ten people (approximately 130 million) in the United States are overweight, close to 90 million are clinically obese and 22 million are morbidly obese.
The definitions of obesity and overweight are somewhat arbitrary. The symptoms of overweight or obesity are characterized by excessive body fat, i.e. the body contains a level of fat beyond that considered normal. Body weight in relationship to height and build is used as a surrogate measure of obesity and overweight. Being 20% over the standard height weight tables is considered obese. The body mass index (BMI) is commonly used in defining normal weight. The BMI is calculated by dividing a subject weight in kilograms by the square of height in meters (kg/m2) or (lbs.×705/inches2). A BMI of 25 is considered normal, a BMI of 26-29 is considered overweight, a BMI of 30-40 is obese, and a BMI>40 is considered morbid. A therapeutic intervention is considered effective if it produces a weight reduction of >10%, or a reduction by >5% if ‘co-morbid’ factors are also improved, e.g. any of the blood analyte concentrations related to IGT, Type 2 Diabetes or dyslipidemia.
Despite the recognized interaction between the various CHD risk factors, the pharmaceutical modalities currently available to treat the symptoms of Type 2 Diabetes generally have had no beneficial effect on hyper- or dyslipidemia; in fact, some of the medicines widely used to treat Type 2 Diabetes, e.g. sulfonylureas, tend to increase hyperlipidemia and may, therefore, further contribute to overweight and obesity, thereby increasing the CHD risk. Conversely, medicines presently available to treat various forms of hyper- or dyslipidemia have little or no impact on IFG, IGT, Type 2 Diabetes, overweight or obesity.
Moreover, no single pharmaceutical agent has been able to treat and correct the entire complex of hyper- or dyslipidemia. Drugs such as clofibrate/gemfibrozil can lower TG levels, but have little or no effect on FFA levels, and no effect on total cholesterol levels. Other drugs may shift the proportion of cholesterol found in the form of low and high density lipoprotein cholesterol. For example, certain drugs may actually increase already elevated levels of low density lipoprotein cholesterol. On the other hand, drugs like lovastatin lower the levels of both total and low density lipoprotein cholesterol, while only slightly increasing the level of high density lipoprotein cholesterol. However, these drugs have no effect on FFA and little or no effect on TG levels.
As a result, it is desirable to provide an improved method for treating the syndrome of coronary heart disease risk factors. A new method for treating the early morning rise in hepatic gluconeogenesis and endogenous glucose production is also desired. In other words, an improved method of treatment is desired that lowers high glucose levels resulting from rises in gluconeogenesis and glucose production, and impaired insulin secretion in patients afflicted with CHD risk factors in humans. A new method is also desired wherein the administration of a drug composition does not require a priming dose.
Lipodystrophy
Congenital lipodystrophy is an uncommon disorder characterized by defective lipid metabolism, accompanied by loss of subcutaneous and/or redistribution of body fat. A novel, acquired form of this disorder is now commonly encountered in up to 80% of HIV-infected patients in general, and particularly those receiving the Highly Active Antiretroviral Therapy (HAART). The introduction of HAART with protease inhibitors and nucleoside reverse transcriptase inhibitors has converted the high mortality Acquired Immuno Deficiency Syndrome (AIDS) to the chronic, high morbidity acquired Lipodystrophy Syndrome (LS). This acquired form of Lipodystrophy (LS) is now recognized not only by its changes in body habitus as a result of fat redistribution, but also as a heterogeneous combination of additional abnormalities, including disturbances in lipid and carbohydrate metabolism. As a result, the suspected pathophysiologic cause and effect relationships, as well as the therapeutic consequences are becoming even more complex.
Lipodystrophy Syndrome and Atherogenic Dyslipidemia
Atherogenic dyslipidemia (AD) is a central defect of the lipodystrophy syndrome, LS, and an independent coronary heart disease risk factor. It is also associated with, and contributing to the pathogenesis of any of the conditions included in this syndrome, including, but not limited to hypertriglyceridemia (HTG), insulin resistance (IR), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM-2). Because of the central role of AD in the progression of the metabolic abnormalities associated with LS, an effective treatment of the LS related form of AD will be of utmost importance. Data for the HIV-uninfected population suggest LS may further include high levels of total cholesterol, low-density-lipoprotein (LDL) cholesterol and triglycerides, and low levels of high-density-lipoprotein (HDL) cholesterol. Because of these established risks, the National Cholesterol Education Program (NCEP) has issued guidelines for the treatment of AD for (non-HIV-infected) patients at risk.
There have been theories as to why lipid abnormalities occur in the HIV-infected population, but these have yet to be verified, and the unknown pathogenesis of dyslipidemia in HIV-infected patients may make them, for a variety of reasons, refractory to traditional pharmacotherapy of atherogenic dyslipidemia. Furthermore, NCEP's emphasis on diet and exercise is unrealistic for many HIV-infected subjects who are struggling to maintain their body weight. This dilemma is further aggravated by the fact that currently available drugs, including bile acid resins, statins, niacin and fibric acid derivatives, to treat hyper- or dyslipidemia pose significant safety risks in HIV-infected patients, particularly those receiving HAART, due to the known incompatibility of these drugs with HAART components, and because of their enhanced liver toxicity in HIV-infected patients, who are already afflicted by severely impaired liver function.